What is genetic engineering?

You are made up of trillions of cells,in a constant state of death and rebirth. Almost all of them carry a blueprint,billions of letters long,known as deoxyribonucleic acid or DNA for short with the instructions for making everything from your eye colour to your heart valves. As your cells replicate and replace themselves,this DNA is copied across,re-encoded. But only the parts relevant to that particular cell,known as genes,switch on. So lung cells are built to take in oxygen while red blood cells are programmed to carry that oxygen around the body.

This is the impressive,if imperfect,engine of all multicellular life on Earth. Sometimes,DNA makes mistakes when copying itself,“mutations”. Most don’t affect how things run. But some can cause problems,like bugs in computer code. And,occasionally,others will make things better. Over time,these good mutations might build up,and their advantages improve generations. That’s what evolution looks like under a microscope.

But now humans have the tools to edit DNA directly,both in living people (known as somatic editing) and embryos not yet born (known as germline editing). This second kind of editing,that so horrified in Dr He’s case,is the easiest way to ensure DNA changes make it to every cell in the body. But any edits will also be permanent;and,critically,pass onto future generations,making the stakes especially high. Right now,researchers agree the technology isnot developed enough to do it safely,and so human germline editing is banned in almost every country.

Indeed,as historian and futurist Yuval Noah Harari writes in his bookSapiens,if we use this technology,humanity will begin to break the laws of natural selection that have shaped life for the past four billion years,and replace them with “laws of true intelligent design”.

Author and geopolitical expert Jamie Metzl,who sits on theWorld Health Organisation’s committee on human gene-editing,agrees it is “the most powerful technology in history” because it can fundamentally change not just individuals,but species. “And it’s[advancing] much faster than most people realise,” he says.

When the Human Genome Project first mapped all six billion letters of our DNA in 2003,it took $US2.7 billion dollars and 13 years. Today,the price of whole genome sequencing (reading someone’s entire genetic code) has already plummeted to less than $600.

“That fall was meant to take six decades,” says Harvard University’s leading geneticist George Church,who has had a hand in everything from the Human Genome Project to CRISPR,and was among the first people on the planet to have their genome sequenced. “Many of the technologies we’re working on now were basically science fiction,only they’ve arrived much sooner than anyone expected.”

One of the key breakthroughs that sped up this clock was CRISPR,a faster,cheaper and more efficient way of editing genes that scientists “borrowed” from bacteria. Jennifer Doudna and Emmanuelle Charpentier were studying the microbes and their impressive ability to edit their own DNA sequences when the scientists hit upon a Nobel-prize-winning idea:that system could be programmed to work in animal and human cells too.

Bacteria live in a constant arms race with viruses,Doudna explains,and so,over millennia,have developed a particularly clever immune system to hunt and destroy viral invaders by searching for their genetic signature. A protein known as CAS9 can cut the viral sequence where it appears in the code. To a virus,this is fatal. But in humans,and other organisms,the double-stranded DNA helix will stitch itself back together again. And so genes can be deleted or even replaced with a new sequence entirely. “I generally describe CRISPR as genetic scissors,” Doudna says. “But you can think of it as search,cut and paste all in one.”

How is gene editing already being used?

Dr He was hardly the first to shock at a genetic engineering conference. In 2017,an amateur “biohacker” famously injected himself with modified DNA mid-talk in the hope it would make him more muscular (it didn’t). And today stories ofglowing rabbits,malaria-resistant mosquitoes andhigh-yield crops (GMOs) are increasingly in the headlines.

In his lab at the University of Sydney,Greg Neely has already been using gene-editing to stop pain in mice,block jellyfish venom hurting humans and even extend the lives of fruit flies. “I don’t want to say how easy it is,or everyone will do it,” Neely quips when he talks about CRISPR.

But,while the tools might be simpler,editing DNA itself is still complicated. For one thing,just as we are more than our genetics,the parts of us that reallyaregenetics rarely come down to just one gene. They are often the sum of many,all working together in ways we don’t quite understand yet. Height,for example,is influenced bymore than 700 genes. Eye colour relies ona dozen,and that’s before we get into the realm of much less tangible traits such asintelligence (and breakdancing prowess). Even the many,many repeats in our DNA,once called “junk DNA”,are now known to play a vital function in regulating how different genes interact.

That makes analysing a genome less like reading computer code and more like following sheet music,Qasim says,where there are marks for breath and pacing and much more. Metzl himself likens the genome to an ecosystem. Mess with one gene,and you might throw off others in places you don’t expect – what scientists call “off target effects”.

Still,while our DNA may be formidably complex,Metzl does not believe it is infinitely so:“We don’t understand it enough yet. That’s what made[Dr He] leaping ahead so shocking ... but it’s not indecipherable magic. We will reach a point where we know enough,we know it’s safe,or worth the risk. Organ donation wasn’t perfect either when it started but it saved lives.”

And when it comes to saving lives,sometimes it really is just one gene scientists need to fix. A single mutation causes conditions such as sickle cell anemia,cystic fibrosis and thedeadly premature ageing disease progeria,putting them well in reach for safe gene therapies,some of which have already been approved by regulators around the world.

When editing the DNA of people already born,Doudna says the hard bit is “getting the CRISPR editing molecules where we need them to go” in the body. “You crack delivery,you open the door to multiple cures.” So far,therapies often involve removing blood or bone marrow to edit cells,then putting it back in the patient,where the tweaked DNA will be carried around the body as the cells replenish themselves. “They’re like blood transfusions,” Qasim says. Sometimes,nanoparticles released into the blood can even do the gene-editingfor doctors inside the body;or a deactivated virus will carry the edits.

Still,it’s not perfect. CRISPR is designed to cut and “whenever you make a break[in DNA],you run the risk of causing damage,mutations,even cancer,” Neely says. “It’s easier to break something than it is to fix it.”

The good news is that scientists are already working on CRISPR upgrades. David Liu and his teams at MIT and Harvard have transformed the CAS-9 scissors to instead act as an eraser and pencil – rather than cutting and replacing the DNA sequence,his “base editing” technique triggers a chemical reaction to actually change the existing letter in the DNA. It can now do this to correct the single gene mutations behind roughly 5000 diseases,and Qasim expects to see many of these therapies go through clinical trials in the next five to 10 years.

But both Qasim and Church still see germline editing as something of a distraction,without a clear medical need at present. Embryos can already be screened for disease using existing IVF procedures. “Of course,you could argue we should be able to inherit our advances too,” Church says. “We made smallpox extinct[with vaccines] and now the entire planet is getting that protection for free.” Doudna can also imagine “a not-too-distant future where germline editing is advanced to the point where it’s safe and accurate. For families that carry hereditary diseases ... they might want to spare future generations from pain and suffering.”

So what about designer babies? And living forever?

Many say here is where we must hold the line:gene-editing should be a rare tool for eliminating serious disease only. But others,including Metzl,see the line between medicine and enhancement as too blurry to last forever. What if a cure for Alzhiemer’s disease came with the side-effect of enhanced memory? Or suppose we could edit out disease altogether - engineering our hearts never to fail,or our cells never to become cancerous?

At Harvard,Church has already made a line of pigs resistant to viruses so they can be raised as safe organ donors for humans. “And that could be done,we think,in all animals eventually,” he says.

Meanwhile,Neely’s lab is searching for the genes that could slow and even stop ageing. By screening the genomes of lucky humans who have lived long lives without disease,the team has identified 800-odd genes at play,and homed in on about 30 which seem particularly significant (many control how well our cells process waste). When they ramp up the same genes in a model species (in this case,fruit flies),the effect is striking. “Fruit flies normally live for about 80 days and we’ve already extended that by about half to 120 days,” Neely says.

Of course,fruit flies are a long way from humans. But if gene-editing could help our species thrive (as every other animal has sought to do when it found an evolutionary advantage),why shouldn’t we use it? What would we be willing to risk,Metzl wonders,for those extra years,those extra lives,the ideas,the art,and the love that wouldn’t have happened otherwise? “With climate change,we may actually need to change ourselves to survive one day,either here or if we colonise other planets like Mars,” he says. “It’s crucial we draw red lines,the way we have for germline editing right now,but we cannot expect those lines to be uncrossable forever.”

Already some IVF clinics around the world allow parents to choose their child’s sex and eye colour and a number of companies are working to create genetic profiles for embryos too. Ifstem cells are one day used to grow viable embryos (instead of eggs being harvested from mothers),the opportunities for such screening will explode,Metzl says. Suddenly,instead of picking from a few dozen embryos,you’d have millions,each with their own combination of genes to peruse. Curly hair over here but a higher chance of musical genius in this embryo here. Better still,both traits combined in the next one over. There may be no need to edit at all.

Current IVF screening has itself reduced the rate of babies born with non-life-threatening conditions such asDown Syndromeand dwarfism,and skewed gender demographics in countries such as India and China. Many fear that disability,not just disease,will increasingly become the target of genetic erasure as the technology advances – embryos likely to have bipolar disorder or deafness may no longer be considered viable either. And it doesn’t take too much imagination to see how a “designer baby” scenario could rapidly open a new and likely unbridgeable class divide between those who can afford to be enhanced and those you cannot (If you can’t quite picture it,watch the filmGattaca).

Metzl himself is intimately aware of the shadow of eugenics hanging over this debate – that now thoroughly discredited push to advance the human race by breeding in or out certain traits. His own father and grandparents fled Nazism in Austria during World War II. “I know what it means to be on one side of someone’s crazy story of what is and isn’t human,” he says. “We must always remember what happened then.”

Rather than another state-sponsored eugenics program,what many fear now is free-market genetics;a strange warping of the survival of the fittest where human evolution is shaped by fads as much as advantage. Some argue it is unethical for a parent to alter their child’s fundamental make-up at all,especially for something like a preference for blue eyes over brown. (“Aesthetic edits should be banned at least,” Neely says.) Others say we have long preferenced parental choice in reproduction laws,such as regulated abortion. But no one has much confidence diversity will be front of mind when genes for high intelligence and super-speed are on the shelves.

The problem is diversity is not just a nice thing for a society – it is crucial to our survival and resilience as a species. “What if we wipe out some gene we thought was defective but really helped us survive a coming plague?” Metzl muses. “Or we make ourselves too homogeneous,we destroy creativity[and] different kinds of intelligence? All our cultural biases could come through ... A country of Captain Americas would actually be weaker because we’d all be the same.”

Yes,now you mention Captain America,what about supersoldiers?

Militaries are often on the cutting edge of research. They have deep pockets and a dubious history of experimenting on their soldiers,from testing chemical weapons during the world wars to strange attempts to develop telekinesis and night vision. (One shadowy program since declassified by the CIA is depicted in the memoir and film The Men Who Stare At Goats.)While Metzl thinks it unlikely a new line of soldiers will be bred from scratch any time soon (rearing them sounds like an awfully big commitment,for one),some say gene-editing on adult soldiers could be closer than we think.

Today,Russia is already analysing the “genetic passports” of its soldiers to determine how best to deploy them. President Vladimir Putin himself has flirted with the idea of supersoldiers,declaring in 2017 that now scientists can break into our genetic code,they may be able to create soldiers without fear or compassion,though he added it needed an ethical foundation. Meanwhile,the US military has abandoned its“Iron Man” robotic exoskeleton for soldiers,but continues to invest in genetic research,engineering mice to withstand nerve agents in 2020.France has started its own supersoldier research too,including into brain chips and tolerance to pain and stress. (“Not everyone shares our scruples and we must be prepared,” Defence Minister Florence Parly said.) And China experts Elsa Kania and Wilson VornDick saysignificant Chinese research into the military application of gene-editing has been linked back to the country’s ruling Communist Party.

If we are to take the typical sci-fi supersoldier as our guide,your Captain America,then we could expect super strength and endurance to be traits in hot demand by militaries around the world. They are also traits likely to be at least partially in reach – 200-odd genes influencing athleticism have already been identified. By deleting a gene that normally dampens muscle growth,for example,Chinese scientists were able to double the rig on a litter of dogs in 2015. Then there’s the strange case of Finland’s champion skier Eero Mäntyranta who was always being accused of doping. When Mäntyranta happened to have his genome sequenced,he discovered he and his family actually shared a rare mutation which allowed red blood cells to better carry oxygen,naturally improving endurance.

“I’d say a few of the best athletes probably have something weird going on[genetically],” Neely laughs.

Perhaps one day we will have to ban “genetic doping” internationally the way we screen for drug performance enhancers now. Or people will seek to borrow traits from other species – say the endurance of a wolf,not just a champion skier,or the speed of a cheetah? Even more imaginatively,Marvel’s superhero series Luke Cagefeatures a hero whose genome has been fused with that of a shellfish (using CRISPR no less).

All animals and plants are made of DNA,just as we are,so you really can copy and paste genes across species lines,Neely says. In 2020,inspired by some rather woeful attempts to farm spiders for their bulletproof silk,scientistsspliced the spider’s silk-making protein into goats instead. When the goats produced milk,out came the protein needed to spin the fabric.

Of course,the genes that give a cheetah its speed may act completely differently if dumped into a human,Neely says. “You could have a whole lot of nightmare mistakes in between.” RememberThe Island of Dr Moreau?

Well,it’s being regulated,right?

Gene therapies,such as the kind Qasim is trialling on leukemia patients,are often a last resort and face the same rigorous safety testing as any medicine. But the rules forgenetically engineering plants and animals are looser. And,while China has moved to tighten its own laws on human editing since the 2018 scandal,Metzl says it’s still something of a “wild west”. “There’s a lot of pressure to be first.”

Some have suggested an enforced ban on human germline editing along the lines of current nuclear arms bans may be in order. Metzl agrees gene-editing is as powerful,as serious,as nuclear weapons. (“Once we start[down enhancement] we could have an arms race of the human race,” he says.) But,unlike warheads,there are real benefits to its use too - curing disease,helping feed the world. “We’re not talking aboutkiller robots here. We don’t want to[stifle] innovation.”

And how would you enforce a ban? Imagine if one nation decided to go rogue and alter the human genome. Would others then invade to stop them? In his bookHacking Darwin,Metzl argues a country looking to keep edited humans from crossing its borders would have to become almost a dictatorship itself,running intrusive genetic screening.

Instead,as a guide for regulation,many point to IVF,which was also feared to some degree when it arrived some 40 years ago. (A media storm even engulfed the British scientists who created the first “test tube baby” Louise Brown in 1978.) “If you’d called for an international ban on IVF[before Louise was born healthy],most people would have agreed because they thought it was unnatural,” Metzl says. “But how many people are alive today because of IVF? We need to go step by step like we did there.”

Doudna,who was among scientists calling for a moratorium on human germline editing after she developed CRISPR,agrees it’s critically important to establish “international guidelines and guardrails”. “Like any transformative technology,there is a potential for misuse but the ... benefits far outweigh the risks”.

“By far most scientists are responsible,but we can’t just rely on all of them being inherently honourable.”

Of course,regulation itself can get things wrong too. In the early 1900s,before the horrors of the Holocaust were revealed,governments throughout Europe and America were embracing their own eugenics laws. Thousands of people deemed “unfit” to breed,mostly in jail or asylums,were forcibly sterilised.

And,on the other side of those who fear the wider use of gene editing are those who worry what will happen if such technology doesnotbecome common,if plans are not put in place to ensure it is rolled out equally when it is ready. The rich always tend to get first dibs on new technology and it’s already happening with the new CRISPR therapies,Doudna says. “First-generation sickle cell treatments will cost upwards of $US2 million.” Doudna and researchers such as Church,Qasim and Neely are now working to make their techniques more efficient and so drive down costs.

Metzl,who recently spoke at a forum on gene editing at the Vatican,says everyone,of every faith and background,needs to be part of the debate too. “We’re talking about the future of our species. People say[genetic engineering] must be bad because it’s not natural,but what’s natural about say industrialised farming? When you consider what a chicken looks like today compared to 50 years ago,we’ve already created mutants.”

Still it’s OK to be nervous about this brave new world of gene editing. In fact,Church says “people should be nervous”. “It’s when we don’t talk,we’re not open,that things happen.”

We now know that Dr He discussed his plan to make CRISPR babies with a number of scientists,including in the West,before and during the trial (most of whom later claimed they did not know it was actually going ahead). “But no one was listening to him properly,joining the dots,” Church says. “There was no immune response. We need better surveillance,an early warning system.”

Metzl agrees:“By far most scientists are responsible,but we can’t just rely on all of them being inherently honourable.”

After all,even the scientist inFrankenstein thought he was improving humanity when he created his monster. Mary Shelley wrote that story,to warn us of the dangers of playing God,in 1818.

Today,the technology is here,Metzl says. It’s no longer a yes or no question.

“If we turn it into one,then either a genetic arms race with no restrictions ends in disaster because we weren’t careful or people are stuck living lives of agony for no reason because we were afraid.”

Also in this sci-fi series ...

• ‘A numbers game’:Will we ever find aliens (and what are UFOs)?
• Brain chips and cyborgs:Will artificial intelligence rule the world?
• Beam me up,Scotty:Will we ever teleport or travel the universe?
• Could we resurrect mammoths,Tassie tigers and dinosaurs?
  

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